DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Formal Matters
Claims 1-31 were originally presented on 12/07/2022. The preliminary amendments to the claims, filed 11/22/2023, have been received and entered. Claims 2, 6-7, 9, 13, 15-16, 18, and 21-23 were cancelled.
Claims 1, 3-5, 8, 10-12, 14, 17, 19-20, and 24-31 are pending and under examination.
Priority
This application is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/US2021/038038, filed June 18, 2021, which claims the benefit of priority under 35 U.S.C. § 119 to U.S. provisional application No. 63/041,577, filed June 19, 2020, and U.S. provisional application No. 63/120,044 filed December 1, 2020.
Information Disclosure Statement
Applicant’s Information Disclosure Statements filed 11/22/2023 and 9/9/2024 have been received and entered into the present application. As reflected by the attached, completed copies of form PTO-1449, the Examiner has considered the cited references to the extent that they comply with the provisions of 37 C.F.R. §1.97, §1.98 and MPEP §609.
Claim Objections
Claim 17 is objected to because of the following informalities: the phrase “and or” in line 7 should be written - - - and/or - - -. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
"The primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent. A secondary purpose is to provide a clear measure of what applicants regard as the invention so that it can be determined whether the claimed invention meets all the criteria for patentability and whether the specification meets the criteria of 35 U.S.C. 112, first paragraph with respect to the claimed invention.", (see MPEP § 2173).
Claims 1, 3-5, 8, 10-12, 14, 17, 19-20, and 24-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claim term “…or the RTX is administered at a concentration and volume such that the intravesical concentration of RTX in the bladder is at least about 0.1 mcg/ml” in claim 1 is unclear and ambiguous. In particular, it is not clear how said intravesical concentration of RTX in the bladder, which is dependent on both the concentration of the RTX solution which is administered as well as on the volume of urine already present in the bladder, is calculated. No method of measuring such an intravesical concentration of RTX in the bladder has been provided by Applicants. For example, if 0.2 mcg/ml of RTX is intravesically administered to an empty bladder, the intravesical concentration of RTX in the bladder would be 0.2 mcg/ml. However, if some amount of urine is present in the bladder prior to administering RTX, the concentration of RTX administered will be diluted to some unknown degree such that the intravesical concentration of RTX in the bladder is less than the administered concentration. It is unclear how a person of ordinary skill in the art would measure or know the volume of urine already present in the bladder of a subject before intravesically administering RTX to the subject. For example, it is unclear if the claims require flushing and emptying the bladder before RX administration such that the RTX is administered to a completely empty bladder. As the volume of urine in the bladder would be required to be known a priori to calculate whether or not the intravesical concentration of RTX in the bladder is at least about 0.1 mcg/ml, the metes and bounds of the claims are indefinite under 35 U.S.C. 112(b).
Claim 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 recites the limitation “of the maladaptive pain" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 4 depends directly from claim 1, which recites treating bladder pain or bladder cancer. There is no mention or requirement that the bladder pain in claim 1 is “maladaptive pain”, rendering it unclear what maladaptive pain is being referred to in claim 4.
Claims 17 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 17, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 19, the phrase "for example" [“e.g.”] renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by IGAWA ET AL. (37th Annual Conference of the International Continence Society – Rotterdam, August 24, 2007, “Intravesical High-Dose Resiniferatoxin for the Treatment of Interstitial Cystitis”, Abstract 423, 2 pages) as evidenced by YOSHIMURA ET AL. (International Journal of Urology, 2014, vol. 21, Suppl. 1, p.18-25).
IGAWA ET AL. teach intravesical administration of 100 mL of 1 mM resiniferatoxin (RTX) is effective to improve pain and to increase voided volume in human subjects [women] having interstitial cystitis1.
“The study enrolled nine women…with IC [interstitial cystitis]…”
(p.1, “Study design, materials and methods”)
“RTX…was dissolved with 100% ethanol at a concentration of 100 microM as a stock solution…and 1 ml of the RTX stock solution was diluted with 99 ml of normal saline…to make 100 ml of 1 microM of RTX.”
(p.1, “Study design, materials and methods”)
“The patients were received intravesical RTX instillation at the operation theatre.”
(p.1, “Study design, materials and methods”)
“…100 ml of 10 microM [sic – 1 microM] as a 1% ethanolic solution was administered intravesically by drip instillation...for 3-4 min.”
(p.1, “Study design, materials and methods”)
“The pain scale improved in all patients at 4 weeks after treatment, and the average pain scale significantly improved from 7.89 1.96 before treatment to 3.33 3.36…and 3.67 3.46…at 4 and 12 weeks after treatment…”
(p.1, “Results”)
They teach the intravesical RTX at a dose of 1 microM was 10-100 times higher than the highest concentration reported by the previous studies (p.1, “Interpretation of results”). The amount of RTX administered intravesically corresponds to 62.87 mcg and a concentration of 0.629 mcg/ml.
1 x 10-6 mol/L [1 microM] * 100 x 10-3 L = 100 x 10-9 mol
100 x 10-9 mol * 628.718 g/mol = 62.87 x 10-6 g = 62.87 mcg
62.87 mcg/100 mL = 0.629 mcg/mL
The dose (62.87 mcg), concentration (0.629 mcg/ml), and volume (100 mL) of RTX intravesically administered to the empty bladders of women having interstitial cystitis anticipates claims 1, 14, 17, 19-20, and 27.
Regarding claim 8, YOSHIMURA ET AL. is cited as evidence that interstitial cystitis “…is associated with stress-based activation of C fibers”. In this regard, they teach pain is a defining characteristic of BPS/IC. One mechanism by which pain is induced is postulated to involve chronic tissue inflammation that can lead to functional changes in C-fiber afferents. Hyperactivity and emergence of mechanosensitivity of C-fiber afferents might lead to pain sensation in response to normal non-noxious distension of the bladder (p.18, 2nd full paragraph).
Regarding claim 12, it is common knowledge in the art that interstitial cystitis is characterized by and causes, inter alia, a frequent, urgent need to urinate. Such is also evidenced by YOSHIMURA ET AL., who teach that BPS/IC is a debilitating chronic disease characterized by suprapubic pain related to bladder filling, coupled with additional symptoms, such as increased day- and night-time urinary frequency, without proven urinary infection or other obvious pathology (p.18, 1st full paragraph).
Accordingly, IGAWA ET AL. anticipate claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29
Claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29 are rejected under 35 U.S.C. 103(a) as being unpatentable over IGAWA ET AL. (37th Annual Conference of the International Continence Society – Rotterdam, August 24, 2007, “Intravesical High-Dose Resiniferatoxin for the Treatment of Interstitial Cystitis”, Abstract 423, 2 pages) as evidenced by YOSHIMURA ET AL. (International Journal of Urology, 2014, vol. 21, Suppl. 1, p.18-25).
Bladder pain can occur in a number of conditions, including idiopathic cystitis and bladder cancer and in such conditions can be maladaptive, i.e., pain that does not correlate to a present injury or other external pain source (Specification at [003]). RTX has been investigated previously for treatment of bladder pain, but the results of such studies were purportedly contradictory and did not support a clear conclusion as to RTX efficacy (Specification at [008]). Applicants disclose that they recognized that increased dosages relative to those used in previous studies more effectively ablate neurons and are therefore considered more effective (Specification at [0012]).
IGAWA ET AL. teach intravesical administration of 100 mL of 1 mM resiniferatoxin (RTX) is effective to improve pain and to increase voided volume in human subjects [women] having interstitial cystitis2.
“The study enrolled nine women…with IC [interstitial cystitis]…”
(p.1, “Study design, materials and methods”)
“RTX…was dissolved with 100% ethanol at a concentration of 100 microM as a stock solution…and 1 ml of the RTX stock solution was diluted with 99 ml of normal saline…to make 100 ml of 1 microM of RTX.”
(p.1, “Study design, materials and methods”)
“The patients were received intravesical RTX instillation at the operation theatre.”
(p.1, “Study design, materials and methods”)
“…100 ml of 10 microM [sic – 1 microM] as a 1% ethanolic solution was administered intravesically by drip instillation...for 3-4 min.”
(p.1, “Study design, materials and methods”)
“The pain scale improved in all patients at 4 weeks after treatment, and the average pain scale significantly improved from 7.89 1.96 before treatment to 3.33 3.36…and 3.67 3.46…at 4 and 12 weeks after treatment…”
(p.1, “Results”)
They teach the intravesical RTX at a dose of 1 microM was 10-100 times higher than the highest concentration reported by the previous studies (p.1, “Interpretation of results”). The amount of RTX administered intravesically corresponds to 62.87 mcg and a concentration of 0.629 mcg/ml.
1 x 10-6 mol/L [1 microM] * 100 x 10-3 L = 100 x 10-9 mol
100 x 10-9 mol * 628.718 g/mol = 62.87 x 10-6 g = 62.87 mcg
62.87 mcg/100 mL = 0.629 mcg/mL
The dose (62.87 mcg), concentration (0.629 mcg/ml), and volume (100 mL) of RTX intravesically administered to the empty bladders of women having interstitial cystitis anticipates claims 1, 14, 17, 19-20, and 27.
Regarding claim 8, YOSHIMURA ET AL. is cited as evidence that interstitial cystitis “…is associated with stress-based activation of C fibers”. In this regard, they teach pain is a defining characteristic of BPS/IC. One mechanism by which pain is induced is postulated to involve chronic tissue inflammation that can lead to functional changes in C-fiber afferents. Hyperactivity and emergence of mechanosensitivity of C-fiber afferents might lead to pain sensation in response to normal non-noxious distension of the bladder (p.18, 2nd full paragraph).
Regarding claim 12, it is common knowledge in the art that interstitial cystitis is characterized by and causes, inter alia, a frequent, urgent need to urinate. Such is also evidenced by YOSHIMURA ET AL., who teach that BPS/IC is a debilitating chronic disease characterized by suprapubic pain related to bladder filling, coupled with additional symptoms, such as increased day- and night-time urinary frequency, without proven urinary infection or other obvious pathology (p.18, 1st full paragraph).
Because Igawa et al. anticipates claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29 (see 35 U.S.C. 102(a)(1) rejection supra), the Examiner similarly concludes that these claims are also obvious over Igawa et al. See In re McDaniel, 293 F.3d 1379, 1385 (Fed. Cir. 2002) (holding that “[i]t is well settled that ‘anticipation is the epitome of obviousness”’ (quoting Connell v. Sears Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983)).
Claim 10
Claim 10 is rejected under 35 U.S.C. 103(a) as being unpatentable over IGAWA ET AL. (37th Annual Conference of the International Continence Society – Rotterdam, August 24, 2007, “Intravesical High-Dose Resiniferatoxin for the Treatment of Interstitial Cystitis”, Abstract 423, 2 pages) as evidenced by YOSHIMURA ET AL. (International Journal of Urology, 2014, vol. 21, Suppl. 1, p.18-25) as applied to claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29 above, and further in view of LIU ET AL. (BJU International, 2007, vol.100, no.7, p.1086-1090) (ABSTRACT attached).
The teachings of Igawa et al. and Yoshimura et al. as applied to claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29 supra are herein incorporated by reference in their entirety and applied equally to claim 10.
Claim 10 differs from Igawa et al. in so far as Igawa et al. does not disclose administering RTX to subjects who previously underwent bladder surgery.
LIU ET AL. teach that transcript levels of TRPV1 in the bladder before treatment with intravesical resiniferatoxin correlated significantly with the therapeutic effect of resiniferatoxin, with higher TRPV1 mRNA expression in responders than nonresponders. They teach bladder wall biopsies were taken from the posterior wall by rigid cystoscopy and TRPV1 expression in the bladder wall samples was determined by rtPCR and immunohistochemical staining (Abstract). They conclude that successful intravesical resiniferatoxin treatment is closely associated with the over-expression of TRPV1 in the bladder mucosa and submucosa in patients with idiopathic detrusor overactivity.
It would be obvious to a person of ordinary skill in the art to intravesically administer RTX in the high dose taught in Igawa et al. to treat bladder pain in patients who previously underwent bladder surgery, e.g., a bladder wall biopsy taken from the posterior wall by rigid cystoscopy as taught in Liu et al. Because TRPV1 expression in the bladder wall correlates to therapeutic efficacy of resiniferatoxin (Liu et al.), a person of ordinary skill in the art would have a reasonable expectation of success in first taking a bladder wall biopsy and determining TRPV1 expression and subsequently intravesically administering resiniferatoxin as suggested and motivated by the combined teachings of the cited prior art. Such administration to a subject who previously underwent a bladder biopsy [surgery] would reasonably be expected to provide the same therapeutic benefits, i.e., pain reduction as taught in Igawa et al. and improvement of urgency scale as taught in Liu et al., as a subject who had not previously undergone bladder surgery.
Claim 11
Claim 11 is rejected under 35 U.S.C. 103(a) as being unpatentable over IGAWA ET AL. (37th Annual Conference of the International Continence Society – Rotterdam, August 24, 2007, “Intravesical High-Dose Resiniferatoxin for the Treatment of Interstitial Cystitis”, Abstract 423, 2 pages) as evidenced by YOSHIMURA ET AL. (International Journal of Urology, 2014, vol. 21, Suppl. 1, p.18-25) as applied to claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29 above, and further in view of WO 99/09970 (Published March 4, 1999).
The teachings of Igawa et al. and Yoshimura et al. as applied to claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29 supra are herein incorporated by reference in their entirety and applied equally to claim 11.
Claim 11 differs from Igawa et al. in so far as Igawa et al. does not disclose administering RTX to subjects with bladder pain subsequent to an injury, e.g., an injury to the spine.
WO ‘970 teaches methods of treating neurogenic urinary dysfunction comprising contacting urinary bladder mucosa of a patient with an effective dose of a homovanilloid compound, including RTX (Abstract). The method includes treatment of urge incontinence due to detrusor hyperreflexia (DH) and treatment of sensory hypersensitivity of the bladder resulting from prostate hypertrophy or interstitial cystitis (Abstract).
Common neurologic disorders associated with DH include, inter alia, spinal cord injury as recited in claim 11 (paragraph bridging p.1-2). Working examples of WO ‘970 include intravesically administering RTX to patients having spinal cord injury (p.7, l.24 to p.12, l.25).
It would be obvious to a person of ordinary skill in the art to intravesically administer RTX in the high dose taught in Igawa et al. to treat bladder pain to patients who have urge incontinence due to a spinal cord injury. Such administration would reasonably be expected to provide at least two benefits to such a patient: relief of bladder pain (Igawa et al.) and urinary incontinence (WO ‘970).
Claims 30-31
Claims 30-31 are rejected under 35 U.S.C. 103(a) as being unpatentable over IGAWA ET AL. (37th Annual Conference of the International Continence Society – Rotterdam, August 24, 2007, “Intravesical High-Dose Resiniferatoxin for the Treatment of Interstitial Cystitis”, Abstract 423, 2 pages) as evidenced by YOSHIMURA ET AL. (International Journal of Urology, 2014, vol. 21, Suppl. 1, p.18-25) as applied to claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29 above, and further in view of US 2019/0076396 A1 (Published March 14, 2019) and SAITOH ET AL. (The Journal of Urology, 2008, vol. 179, p.359-364).
The teachings of Igawa et al. and Yoshimura et al. as applied to claims 1, 3-5, 8, 12, 14, 17, 19-20, 24, and 26-29 supra are herein incorporated by reference in their entirety and applied equally to claims 30-31.
Claims 30-31 differ from Igawa et al. in so far as Igawa et al. administered RTX dissolved in saline and does not teach the carrier further comprised polysorbate 80 and/or a buffer.
Formulating RX for intravesical administration to the bladder in a carrier comprising polysorbate 80 and/or a buffer would have been obvious and routine to a person of ordinary skill in the art. US ‘396 teaches safer formulations of resiniferatoxin (RTX) that are alcohol free comprising a solubilizing component, a monosaccharide or sugar alcohol, a saline buffer, and RTX, and having narrow ranges for pH range and specific gravity (Abstract). Specifically, they teach formulations comprising 200 mg/mL RTX, polysorbate 80, dextrose or mannitol, and 30 mM phosphate buffer and having pH 7.2 (Table 1). While US ‘396 does not disclose intravesical administration of the formulations disclosed therein, SAITOH ET AL. teach intravesical instillation of RTX diluted to desired concentrations in 10% ethanol, 10% Tween 80 [polysorbate 80], and 80% saline (Abstract; paragraph bridging p.360-361).
Accordingly, a person of ordinary skill in the art would have had a reasonable expectation of success in formulating RTX for intravesical administration using pharmaceutically acceptable carriers such as water or saline that further comprise polysorbate 80 and/or a buffer. Such formulations provide a high concentration of RTX and would be expected to be less toxic to cells, particularly nerve cells, due to the absence of an alcohol as a solubilizing agent as taught by US ‘396.
Conclusion
Applicant is requested to specifically point out the support for any amendments made to the disclosure in response to this Office action, including the claims (M.P.E.P. §§ 714.02 and 2163.06). In doing so, applicant is requested to refer to pages and line (or paragraph) numbers (if available) in the as-filed specification, not the published application. Due to the procedure outlined in M.P.E.P. § 2163.06 for interpreting claims, other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Applicant is reminded that MPEP §2001.06(b) clearly states that “[t]he individuals covered by 37 C.F.R. 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question." See Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972). MPEP §2001.06(b) clearly indicates that “if a particular inventor has different applications pending in which similar subject matter but patentably indistinct claims are present that fact must be disclosed to the examiner of each of the involved applications.” See Dayco Prod. Inc. v. Total Containment, Inc., 329 F.3d 1358, 1365-69, 66 USPQ2d 1801, 1806-08 (Fed. Cir. 2003).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES D ANDERSON whose telephone number is (571)272-9038. The examiner can normally be reached on Monday-Friday, 7:30 am - 4:00 pm PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/James D. Anderson/Primary Examiner, Art Unit 1629
UNITED STATES PATENT AND TRADEMARK OFFICE
500 Dulany Street
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Tel. No.: (571) 272-9038
1 Interstitial cystitis is the common term for “maladaptive bladder pain”, i.e., bladder pain that does not correlate to a present injury or other external pain source.
2 Interstitial cystitis is the common term for “maladaptive bladder pain”, i.e., bladder pain that does not correlate to a present injury or other external pain source.